The present invention provides novel intermediates and chemical processes which are useful in preparing side chain and skeletal analogs of Thromboxane B.sub.2 (TXB.sub.2).
Some material essential to disclosure of the present invention is incorporated here by reference from Ser. No. 676,890, filed Apr. 14, 1976, now issued as U.S. Pat. No. 4,020,173, on Apr. 26, 1977, as hereinafter indicated.
Thromboxane B.sub.2 has the structure: ##STR1## and can be considered as a derivative of thromboxanoic acid or 11.alpha.-homo-11.alpha.-oxa-prostanoic acid which has the following structure and carbon atom numbering: ##STR2##
A systematic name for thromboxanoic acid is 7-[2.beta.-octyl-tetrahydropyran-3.alpha.-yl]-heptanoic acid.
By way of comparison prostanoic acid has the structure and carbon atom numbering ##STR3## and systematic name: 7-[2.beta.-octyl-cyclopenta-1.alpha.-yl]-heptanoic acid.
Alternatively Thromboxane B.sub.2 is named as an analog of of PGF.sub.2.sbsb..alpha., i.e., 11.alpha.-homo-11.alpha.-oxa-PGF.sub.2.sbsb..alpha..
In the above formulas, as well as in the formulas hereinafter given, broken line attachments to a tetrahydropyran ring or cyclopentane indicate substituents in alpha configuration i.e., below the plane of the ring. Heavy solid line attachments to a tetrahydropyran ring or cyclopentane indicate substituents in beta configuration, i.e., above the plane of the ring. The use of wavy lines (.about.) herein will represent attachment of substituents in either the alpha or beta configuration or attachment in a mixture of alpha and beta configurations. See especially the discussion below pertaining to anomeric mixtures.
The side-chain hydroxy at C-15 in the above formula of TXB.sub.2 is in S configuration. See, Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins, which discussion applies hereto with respect to TXB.sub.2. Expressions such as C-15, and the like, refer to the carbon atom in the thromboxane- or prostaglandin-type compound which is in the position corresponding to the position of the same number in thromboxanoic acid or prostanoic acid, respectively.
Molecules of the known prostaglandins each have several centers of asymmetry, and can exist in racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e. the dextrorotatory and levorotatory forms. Likewise TXB.sub.2, which as disscussed above is alternatively nominated as 11.alpha.-homa-11.alpha.-oxa-PGF.sub.2.sbsb..alpha., has similar centers of asymmetry, and thus, likewise can exist in optically active or racemic form. As drawn, the above formula represents the particular optically active form of the TXB.sub.2 as is obtained biosynthetically, for examples, as obtained by Samuelsson, Proc. Nat. Acad. Sci. USA 71, 3400-3404 (1974). The mirror image of each of these formulas represents the other enantiomer of TXB.sub.2. The racemic form of TXB.sub.2 contains equal numbers of both enantiomeric molecules, and one of the above formulas and the mirror image of that formula is needed to represent correctly racemic TXB.sub.2. For convenience hereinafter, use of the term, thromboxane or "TX" or "TXB" will mean the optically active form of that thromboxane-type compound thereby referred to with the same absolute configuration as TXB.sub.2 obtained biosynthetically by Samuelsson. When reference to the racemic form of a thromboxane-type compound is intended, the word "racemic" or "dl" will precede the name, e.g., dl-TXB.sub.2.
The term "thromboxane intermediate" as used herein, refers to any cyclopentane or tetrahydropyran derivative or acyclic compound which is useful in preparing the various skeletal or side chain analogs of TXB.sub.2.
When a formula, as drawn herein, is used to depict a thromboxane intermediate each such formula represents the particular stereoisomer of the thromboxane intermediate which is useful in preparing the TXB analog of the same relative stereochemical configuration as TXB.sub.2 obtained biosynthetically,
The term "thromboxane-type " (TX-type) product, as used herein, refers to each of the various tetrahydropyran derivatives herein which are useful for at least one of the same pharmacological purposes as the TXB.sub.2, as indicated herein.
The formulas, as drawn herein, which depict a thromboxane-type product, each represent the particular stereo-isomer of the thromboxane-type product which is of the same relative stereochemical configuration as TXB.sub.2 obtained biosynthetically.
The term "thromboxane analog," as used herein, represents that stereoisomer of a thromboxane-type product which is of the same relative stereochemical configuration as TXB.sub.2 obtained biosynthetically or a mixture comprising that stereoisomer and the enantiomer thereof. In particular, where a formula is used to depict a thromboxane-type compound herein, the term thromboxane analog refers to the compound of that formula, or a mixture comprising that compound and the enantiomer thereof.
With respect to the asymmetric C-11 position of TXB.sub.2 and the various hemiacetal analogs thereof herein, the hemiacetal structure about C-11 results in the presence of two diastereiomeric forms: the .alpha.-hydroxy and .beta.-hydroxy anomers. Due to the mutarotation resulting from the conversion of TXB.sub.2 or the hemiacetal analogs thereof to the hydroxy-aldehyde form, e.g. ##STR4## the 11-hydroxyl represents an equilibrium mixture of alpha and beta hydroxy anomers in aqueous and certain other solutions, depicted by a .about. OH, herein.
In formulas herein (e.g., formula IV) where a cyclopentane of tetrahydropyran ring is not present, such a ring having been cleaved or to be introduced in subsequent reaction steps, the convention by which substituents about asymmetric centers are depicted as alpha or beta is as defined above, but with respect to the plane of the various atoms which comprised said ring before its cleavage or will comprise said ring as synthesized in subsequent reaction steps. Thus, for example, in formula IV the oxygen atom of the 12-hydroxy substituent, having formerly been or successively to be the 11.alpha.-oxa of the tetrahydrofuran ring is viewed as planar with C-8 to C-11 and C-12. Accordingly the C-12 side chain is beta to this plane and thus rendered by a heavy solid line, while the C-12 hydrogen is alpha to this plane and thus rendered by a dotted line.
Thromboxane B.sub.2 is known in the art. This compound is prepared biosynthetically from arachadonic acid by B. Samuelsson, Proc. Nat, Acad. Sci. U.S.A. 71, 3400-3404 (1974). This compound alternately is named by him as 8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid, hemiacetal or PHD.
TXB.sub.2 is produced biosynthetically from arachadonic acid, employing the cyclic oxygenase system which is responsible for the production of prostaglandins from arachadonic acid.
TXB.sub.2, 15-epi-TXB.sub.2, their 11-(lower alkyl) acetals, acceptable salts have been discovered to be extremely potent in causing various biological responses. For that reason, these compounds (hereinafter TXB.sub.2 compounds) have been found to be useful for pharmacological purposes.
These biological responses include:
a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit duodenum, or gerbil colon); and more especially and particularly
b. affecting the reproductive organs of mammals as labor inducers, abortifacients, cervical dilators, regulators of the estrus, and regulators of the menstrual cycle.
Because of these biological responses, these TXB.sub.2 compounds are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.
These TXB.sub.2 compounds, being extremely potent in causing stimulation of smooth muscle, are also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore, these compounds for example, are useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, the TXB.sub.2 compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50.mu.g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.
The TXB.sub.2 compounds, being useful in place of oxytocin to induce labor, are used in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose of 0.01 to 50 .mu.g. per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. An alternative route of administration is oral.
The compounds are further useful for controlling the the reproductive cycle in menstruating female mammals, including humans. Menstruating female mammals are those mammals which are mature enough to menstruate, but not so old that regular menstruation has ceased. For that purpose the TXB.sub.2 compound is administered systemically at a dose level in the range 0.01 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Intravaginal and intrauterine routes are alternate methods of administration. Additionally, expulsion of an embryo or a fetus is accomplished by similar administration of the compound during the first or second trimester of the normal mammalian gestation. period.
These compounds are further useful in causing cervical dilation in pregnant and nonpregnant female mammals for purposes of gynecology and obstetrics. In labor induction and in clinical abortion produced by these compounds, cervical dilation is also observed. In cases of infertility, cervical dilation produced by these compounds is useful in assisting sperm movement to the uterus. Cervical dilation by thromboxanes is also useful in operative gynecology such as D and C (Cervical Dilation and Uterine Curettage) where mechanical dilation may cause perforation of the uterus, cervical tears, or infections. It is also useful in diagnostic procedures where dilation is necessary for tissue examination. For these purposes, the TXB.sub.2 compound is administered locally or systemically.
TXB.sub.2, for example, is administered orally or vaginally at doses of about 5 to 200 mg. per treatment of an adult female human, with from one to five treatments per 24 hour period. Alternatively TXB.sub.2 is administered intramuscularly or subcutaneously at doses of about one to 25 mg. per treatment. The exact dosages for these purposes depend on the age, weight, and condition of the patient or animal.
These compounds are further useful in domestic animals as an abortifacient (especially for feedlot heifers), as an aid to estrus detection, and for regulation of synchronization of estrus. Domestic animals include horses, cattle, sheep, and swine. The regulation or synchronization of estrus allows for more efficient management of both conception and labor by enabling the herdsman to breed all his females in short pre-defined intervals. This synchronization results in a higher percentage of live births than the percentage achieved by natural control. The TXB.sub.2 compound is injected or applied in a feed at doses of 0.1-100 mg. per animal and may be combined with other agents such as steroids. Dosing schedules will depend on the species treated. For example, mares are given the TXB.sub.2 compound 5 to 8 days after ovulation and return to estrus. Cattle, are treated at regular intervals over a 3 week period to advantageously bring all into estrus at the same time.
Certain 11-oxaprostaglandin-type compounds described above are known in the art. See Belgian Patent 830,423 (Derwent Farmdoc CPI No. 01971X) and Tetrahedron Letters 43:3715-3718 (1975).